Nonsteroidal anti-inflammatory drugs (NSAIDs), represented by aspirin and piroxicam, are used widely as antipyretic analgesic antiphlogistic drugs and are considered to manifest anti-inflammatory effects, such as antipyretic, analgesic, and antiphlogistic effects, by suppressing the production of prostaglandins through inhibitory effects on COX (cyclooxygenase). COXs are enzymes that produce PGH2 (prostaglandin H2) from arachidonic acid, and 2 types of enzymes, referred to as constitutive COX-1 and inducible COX-2, are known to exist. Depending on the cell or tissue of production, PGH2 produced by COX is enzymatically converted to PGE2, PGD2, PGF2α, PGI2 (prostacyclin), or TXA2 (thromboxane A2) (Vane J R and Botting R M, Inflammation Research. 44:1, 1995).
In particular, suppression of PGE2 production among the above-mentioned prostanoids is suggested to be important for NSAIDs to show the effect of the drug, due to the fact that PEG2 among these prostanoids is believed to be deeply involved with inflammatory processes, such as pain generation, fever, and edema, and that it exists as the highest concentration at the site of inflammation (Vane J R and Botting R M, Inflammation Research. 44:1, 1995); moreover, the drug efficacies of anti-PGE2 antibody and NSAIDs are reported to be nearly equal in a rat inflammatory model (Portanova J P, Zhang Y, Anderson G D, Hauser S D, Masferrer J L, Seibert K, Gregory S A, Isakson P C, Journal of Experimental Medicine. 184:883–91, 1996).
On the other hand, NSAIDs, apart from PGE2, also suppress the production of PGD2, PGF2α, PGI2, and TXA2 by inhibiting COX, and thus, may exhibit not only anti-inflammatory effects but also effects based on the suppression of the production of these other prostanoids. For example, childbirth is known to be delayed by the inhibition of uterine contraction at the time of delivery due to suppression of PGF2α production, and blood coagulation is known to be delayed by the suppression of TXA2 production (AHFS Drug Information98, p1571 McEnvoy G K Ed., American Society of Health-System Pharmacists, 1998).
Therefore, substances that specifically inhibit the action of PGE2, such as PGE2 synthase (PGES) inhibitors, are expected to serve as excellent anti-inflammatory drugs with lower side effects, by specifically suppressing PGE2 production without suppressing the production of other prostanoids.
To date, although synthases specific for PGD2, PGF2α, PGI2, and TXA2, respectively, have been identified, those for PGE2 synthase have been suggested to exist but have not yet been identified.
Recently, Per-Johan Jakobsson et al. identified a membrane-bound human PGE2 synthase for the first time (Proc. Natl. Acad. Sci. U.S.A., 96:7220–7225, 1999) (herein, the enzyme is referred to as “PGES-2”).
On the other hand, the existence of other enzymes with characteristics different from the PGES-2 has been also suggested. Specifically, Ogorochi et al. have estimated that PGES-2 and a protein of pI5.4 with PEGS activity existing in the cytoplasm of human brain are identical, because the proteins are purified together with glutathione S-transferase (GST) (Ogorochi T, Ujihara M., and Narumiya S., J. Neurochem., 48:900–909, 1987).